Bicyclic n-arylamides

ABSTRACT

The invention relates to novel bicylic N-arylamides, to a method for the production thereof, and to the use of the same for producing pharmaceuticals for the treatment and/or prophylaxis of diseases and for improving perception, power of concentration, learnig capacity and/or memory retention.

The invention relates to novel bicyclic N-arylamides, to a process forthe preparation thereof and to the use thereof for producing medicamentsfor the treatment and/or prophylaxis of diseases and for improvingperception, concentration, learning and/or memory.

Nicotinic acetylcholine receptors (nAChR) form a large family of ionchannels which are activated by the messenger acetylcholine which isproduced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34,563-582). A functional nAChR consists of five subunits which may bedifferent (certain combinations of α1-9 and ⊕1-4,γ,δ,ε subunits) oridentical (α7-9). This leads to the formation of a diversity of subtypeswhich differ in the distribution in the muscles, the nervous system andother organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).Activation of nAChR leads to influx of cations into the cell and tostimulation of nerve cells or muscle cells. Selective activation ofindividual nAChR subtypes restricts this stimulation to the cell typeswhich have a corresponding subtype and is thus able to avoid unwantedside effects such as, for example, stimulation of nAChR in the muscles.Clinical experiments with nicotine and experiments in various animalmodels indicate that central nicotinic acetylchloline receptors areinvolved in learning and memory processes (e.g. Rezvani and Levin, Biol.Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of thealpha7 subtype (α7 nAChR) have a particularly high concentration inregions of the brain which are important for learning and memory, suchas the hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci.1993, 13, 596-604). The α7 nAChR has a particularly high permeabilityfor calcium ions, increases glutamatergic neurotransmission, influencesthe growth of axons and, in this way, modulates neuronal plasticity(Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).

Certain quinuclidinecarboxanilides are described as antiarrhythmics andlocal anesthetics (cf., for example, FR 1.566.045, GB 1 578 421 andOppenheimer et al. Life Sci. 1991, 48, 977-985).

WO 01/60821 discloses biarylcarboxamides with affinity for the α7 nAChRfor the treatment of learning and perception impairments.

The present invention relates to compounds of the general formula (I)

in which

-   R is a 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ring atoms,    in which m and n are independently of one another 2 or 3,    -   in which p is 1, 2 or 3,    -   and where the bicycloalkyl radical is optionally substituted by        (C₁-C₆)-alkyl,-   R² is 8- to 10-membered heteroaryl, naphthyl or azulenyl, where the    rings are optionally substituted by radicals selected from the group    of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl,    trifluoromethoxy, nitro, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,    (C₁-C₆)-alkylthio, and-   R³ is hydrogen or (C₁-C₆)-alkyl.

The compounds of the invention may exist in stereoisomeric forms whicheither are related as image and mirror image (enantiomers) or which arenot related as image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers or respective mixturesthereof. These mixtures are enantiomers and diastereomers which can beseparated in a known manner into the stereoisomerically pureconstituents.

The compounds of the invention may also be in the form of their salts,solvates or solvates of the salts.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention maybe acid addition salts of the compounds with mineral acids, carboxylicacids or sulphonic acids. Particularly preferred examples are salts withhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, oxalic acid, lactic acid, tartaric acid, citric acid,fumaric acid, maleic acid or benzoic acid.

However, salts which may be mentioned are also salts with conventionalbases, such as, for example, alkali metal salts (e.g. sodium orpotassium salts), alkaline earth metal salts (e.g. calcium or magnesiumsalts) or ammonium salts derived from ammonia or organic amines such as,for example, diethylamine, triethylamine, ethyldiisopropylamine,procaine, dibenzylamine, N-methylmorpholine, dihydro-abiethylamine,1-ephenamine or methylpiperidine.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds which form a complex with solvent molecules bycoordination in the solid or liquid state. Hydrates are a special formof solvates in which the coordination takes place with water.

For the purposes of the present invention, the substituents generallyhave the following meaning:

(C₁-C₆)— and (C₁-C₄)-alkoxy stands for a straight-chain or branchedalkoxy radical respectively having 1 to 6 and 1 to 4 carbon atoms.Preference is given to a straight-chain or branched alkoxy radicalhaving 1 to 4, particularly preferably having 1 to 3, carbon atoms. Thefollowing may be mentioned by way of example and preferably: methoxy,ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

(C₁-C₆)— and (C₁-C₄)-alkyl stand for a straight-chain or branched orbranched alkyl radical having 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkyl radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. The following maybe mentioned by way of example and preferably: methyl, ethyl, n-propyl,isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C₁-C₆)-Alkylthio stands for a straight-chain or branched alkylthioradical having 1 to 6 carbon atoms. Preference is given to astraight-chain or branched alkylthio radical having 1 to 4, particularlypreferably having 1 to 3, carbon atoms. The following may be mentionedby way of example and preferably: methylthio, ethylthio, n-propylthio,isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

The 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ring atoms ispreferably and by way of example: 1-azabicyclo[3.2.1]octyl (isotropane),1-azabicyclo[3.3.1]nonyl (isogranatane), 1-azabicyclo[2.2.2]octyl(quinuclidine).

Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine,chlorine and bromine are preferred. Fluorine and chlorine areparticularly preferred.

8- to 10-membered heteroaryl stands for an aromatic bicyclic radicalhaving 8 to 10, preferably 9 to 10, ring atoms and up to 5, preferablyup to 4, heteroatoms from the series S, O and/or N. The heteroarylradical may be bonded via a carbon atom or heteroatom. The following maybe mentioned by way of example and preferably: indolyl, indazolyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.

If radicals in the compounds of the invention are optionallysubstituted, the radicals may, unless specified otherwise, besubstituted one or more times, identically or differently. Substitutionwith up to three identical or different substituents is preferred.

Preferred compounds of the general formula (I) are those

in which

-   R¹ is 1-azabicyclo[2.2.2]octyl,-   and R² and R³ have the meaning indicated above.

Particularly preferred compounds of the general formula (I) are those

in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   and R² and R³ have the meaning indicated above.

Likewise preferred compounds of the general formula (I) are those

in which

-   R² is 9- to 10-membered heteroaryl or naphthyl, where the rings are    optionally substituted by 1 to 3 radicals selected from the group of    hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,    (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio,-   and R¹ and R³ have the meaning indicated above.

Particularly preferred compounds of the general formula (I) are those

in which

-   R² is indolyl, benzoimidazolyl, benzotriazolyl, benzothiophenyl,    benzofuranyl, quinolinyl, isoquinolyl, benzopyrazinyl,    benzopyrimidinyl, benzopyridizanyl or naphthyl, where the rings are    optionally substituted by 1 to 3 radicals selected from the group of    hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,    (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio,-   and R¹ and R³ have the meaning indicated above.

Very particularly preferred compounds of the general formula (I) arethose

in which

-   R² is benzotriazolyl, benzothiophenyl, quinolinyl, benzopyrazinyl or    naphthyl, where the rings are optionally substituted by 1 to 3    radicals selected from the group of hydrogen, halogen, cyano,    trifluoromethyl, trifluoromethoxy, nitro, (C₁-C₄)-alkyl,    (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio,-   and R¹ and R³ have the meaning indicated above.

Likewise preferred compounds of the general formula (I) are those

in which

-   R³ is hydrogen or methyl,-   and R¹ and R² have the meaning indicated above.

Particularly preferred compounds of the general formula (I) are those

in which

-   R³ is hydrogen,-   and R¹ and R² have the meaning indicated above.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

Likewise very particularly preferred are compounds of the generalformula (I)

in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   R² is benzotriazolyl, benzothiophenyl, quinolinyl, benzopyrazinyl or    naphthyl, where the rings are optionally substituted by 1 to 3    radicals selected from the group of hydrogen, halogen, cyano,    trifluoromethyl, trifluoromethoxy, nitro, (C₁-C₄)-alkyl,    (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, and-   R³ is hydrogen.

The invention further relates to a process for preparing the compoundsof the formula (I), characterized in that

-   compounds of the general formula (II)    R¹—CO—X  (II)    in which R¹ has the abovementioned meaning, and-   X is hydroxyl or a suitable leaving group,-   are reacted with a compound of the general formula (III)    HNR¹R²  (III)    in which-   R² and R³ have the abovementioned meaning,-   in an inert solvent, where appropriate in the presence of a    condensing agent and where appropriate in the presence of a base.

If X is a leaving group, chloro, mesyloxy and isobutyloxycarbonyloxy, inparticular chloro, are preferred.

Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, or other solvents such as nitromethane, ethyl acetate,acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane,dimethyl sulfoxide, acetonitrile or pyridine, with preference fortetrahydrofuran, dimethylformamide or chloroform.

Condensing agents are, for example, carbodiimides such as, for example,N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-di-methylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexyl-carbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxy-tri(dimethyl-amino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures thereof.

It may be advantageous where appropriate to use these condensing agentsin the presence of an auxiliary nucleophile such as, for example,1-hydroxybenzotriazole (HOBt).

Examples of bases are alkali metal carbonates and bicarbonates such as,for example, sodium or potassium carbonate or bicarbonate, or organicbases such as alkylamines, e.g. triethylamine, or N-methylmorpholine,N-methylpiperidine, 4-dimethylamino-pyridine or diisopropylethylamine.

Particular preference is given to the combination ofN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)and/or 1-hydroxybenzotriazole (HOBt) in dimethylformamide.

Particular preference is given to the combination ofN,N′-diisopropylcarbodiimide (IDC) and pentafluorophenol in DCM or DMF.The use of tetrafluorophenol and N,N′-diisopropylcarbodiimide (IDC)bonded to resin is likewise particularly preferred (synthetic scheme 1).The preparation of the tetrafluorophenol bonded to resin and the usethereof preferably takes place as described by Salvino et al. J. Comb.Chem. 2000, 6, 691-697.

The process of the invention is preferably carried out in a temperaturerange from room temperature to 50° C. under atmospheric pressure.

The compounds of the general formulae (II) and (III) are known or can besynthesized by known processes from the appropriate precursors (cf., forexample, Comprehensive Heterocyclic Chemistry, Katritzki et al.,editors.; Elsevier, 1996).

Thus, for example, compounds of the formula (II) can be prepared byprocesses known from the literature.

3-Quinuclidinecarboxylic acid hydrochloride: Orlek et al. J. Med. Chem.1991, 34, 2726.

2-Quinuclidinecarboxylic acid hydrochloride: Gassmann and Fox, J. Org.Chem. 1967, 32, 480.

Compounds of the formula (III) can be obtained from the correspondingcarboxylic acids by reactions known to the skilled worker. Thus,anilines can be prepared by, for example, Curtius or Hoffmanndegradation from carboxylic acids or derivatives thereof (cf. forexample, Organikum', Wiley-VCH; 1999). It is particularly suitable touse diphenyl phosphorazidate (DPPA) to generate the isocyanate whichoccurs as intermediate and which subsequently reacts with water to givethe target compound. (T. Shioiri and S. Yamada, Chem. Pharm. Bull. 1974,22, 859; Shioiri et al. J. Am. Chem. Soc 1972, 94, 6203.

The compounds of the invention of the general formula (I) are suitablefor use as medicaments for the treatment and/or prophylaxis of diseasesin humans and/or animals.

The compounds of the invention show a valuable range of pharmacologicaleffects which could not have been predicted.

They are notable as ligands, especially agonists, on the α7 nAChR.

The compounds of the invention can, because of their pharmacologicalproperties, be employed alone or in combination with other medicamentsfor the treatment and/or prevention of cognitive impairments, especiallyof Alzheimer's disease. Because of their selective effect as α7 nAChRagonists, the compounds of the invention are particularly suitable forimproving perception, concentration, learning or memory, especiallyafter cognitive impairments like those occurring for example insituations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memoryloss, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post-stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, attentiondeficit hyperactivity disorder, Alzheimer's disease, vascular dementia,Lewy body dementia, dementia with degeneration of the frontal lobes,including Pick's syndrome, Parkinson's disease, progressive nuclearpalsy, dementia with corticobasal degeneration, amyotrophic lateralsclerosis (ALS), Huntington's disease, multiple sclerosis, thalamicdegeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia,schizophrenia with dementia or Korsakoffs psychosis.

The compounds of the invention can be employed alone or in combinationwith other medicaments for the prophylaxis and treatment of acute and/orchronic pain (for a classification, see “Classification of Chronic Pain,Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms”,2nd edition, Meskey and Begduk, editors; IASP Press, Seattle, 1994),especially for the treatment of cancer-induced pain and chronicneuropathic pain like, for example, that associated with diabeticneuropathy, postherpetic neuralgia, peripheral nerve damage, centralpain (for example as a consequence of cerebral ischaemia) and trigeminalneuralgia, and other chronic pain such as, for example, lumbago,backache (low back pain) or rheumatic pain. In addition, these activeingredients are also suitable for the therapy of primary acute pain ofany origin and of secondary states of pain resulting therefrom, and forthe therapy of states of pain which were formerly acute and have becomechronic.

The in vitro effect of the compounds of the invention can be shown inthe following assays:

1. Determination of the Affinity of Test Substances for α7 nAChR byInhibition of [³H]-methyllycaconitine Binding to Rat Brain Membranes

The [³H]-methyllycaconitine binding assay is a modification of themethod described by Davies et al. (Neuropharmacol. 1999, 38, 679-690).

Rat brain tissue (hippocampus or whole brain) is homogenized inhomogenization buffer (10% w/v, 0.32 M sucrose, 1 mM EDTA, 0.1 mMphenylmethylsulphonyl fluoride. (PMSF), 0.01% (w/v) NaN₃, pH 7.4, 4° C.)at 600 rpm in a glass homogenizer. The homogenate is centrifuged(1000×g, 4° C., 10 min) and the supernatant is removed. The pellet isresuspended (20% w/v) and the suspension is centrifuged (1000×g, 4° C.,10 min). The two supernatants are combined and centrifuged (15 000×g, 4°C., 30 min). The pellet obtained in this way is referred to as the P2fraction.

The P2 pellet is washed twice with binding buffer (50 mM Tris-HCl, 1 mMMgCl₂, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, pH 7.4), and centrifuged (15000×g, 4° C., 30 min).

The P2 membranes are resuspended in binding buffer and incubated in avolume of 250 μl (amount of membrane protein 0.1-0.5 mg) in the presenceof 1-5 nM [³H]-methyllycaconitine 0.1% (w/v) BSA (bovine serum albumin)and various concentrations of the test substance at 21° C. for 2.5 h.The non-specific binding is determined by incubation in the presence of1 μM α-bungarotoxin or 100 μM nicotine or 10 μM MLA(methyllycaconitine).

The incubation is stopped by adding 4 ml PBS (20 mM Na₂HPO₄, 5 mMKH₂PO₄, 150 mM NaCl, pH 7.4, 4° C.) and filtering through type A/E glassfibre filters (Gelman Sciences) which have previously been placed in0.3% (v/v) polyethyleneimine (PEI) for 3 h. The filters are washed twicewith 4 ml of PBS (4° C.), and the bound radioactivity is determined byscintillation measurement. All the assays are carried out in triplicate.The dissociation constant K_(i) of the test substance was determinedfrom the IC₅₀ of the compounds (concentration of the test substance atwhich 50% of the ligand bound to the receptor is displaced), thedissociation constant K_(D) and the concentration L of[³H]-methyllycaconitine using the equation K_(i)=IC₅₀/(1+L/K_(D)).

In place of [³H]-methyllycaconitine it is also possible to employ otherα7 nAChR-selective radioligands such as, for example,[¹²⁵I]-α-bungarotoxin or nonselective nAChR radioligands together withinhibitors of other nAChRs.

The suitabilitiy of the compounds of the invention for the treatment ofcognitive impairments can be shown in the following animal models:

2. Object Recognition Test

The object recognition test is a memory test. It measures the ability ofrats (and mice) to distinguish between familiar and unfamiliar objects.

The test is carried out as described by Blokland et al., NeuroReport1998, 9, 4205-4208; A. Ennaceur, J. Delacour,. Behav. Brain Res. 1988,31, 47-59; A. Ennaceur, K. Meliani., Psychopharmacology 1992, 109,321-330; and Prickaerts et al., Eur. J. Pharmacol. 1997, 337, 125-136.

In a first run, a rat is confronted in an otherwise empty observationarena of relatively large size by two identical objects. The rat willinvestigate, i.e. sniff round and touch, both objects extensively. In asecond run, after an interval of 24 hours, the rat is put in theobservation arena again. One of the familiar objects has now beenreplaced by a new, unfamiliar object. If a rat recognizes the familiarobject, it will concentrate on investigating the unfamiliar object.However, after 24 hours, a rat has normally forgotten which object itinvestigated in the first run, and it will therefore inspect bothobjects to the same extent. Administration of a substance with alearning-and memory-improving effect may lead to a rat recognizing theobject seen in the first run 24 hours previously as familiar. It willinvestigate the new, unfamiliar object in more detail than the familiarone. This memory ability is expressed in a discrimination index. Adiscrimination index of zero means that the rat investigates bothobjects, the old and the new, for equal times; that is to say it has notrecognized the old object and reacts to both objects as if they wereunfamiliar and new. A discrimination index greater than zero means thatthe rat inspects the new object longer than the old one; that is to saythe rat has recognized the old object.

3. Social Recognition Test:

The social recognition test is a test to examine the learning- ormemory-improving effect of test substances.

Adult rats housed in groups are placed singly in test cages 30 minutesbefore the start of the test. Four minutes before the start of the test,the test animal is put in an observation box. After this adaptationtime, a juvenile animal is put in with the test animal and the time forwhich the adult animal investigates the juvenile animal is measured for2 minutes (trial 1). All behaviours clearly directed at the young animalare measured, i.e. anogenital inspection, pursuit and fur care, duringwhich the old animal is no further than 1 cm from the young animal. Thejuvenile animal is then taken out, and the adult is left in its testcage (for 24-hour retention, the animal is returned to its home cage).The test animal is treated with substance before or after the firsttest. Depending on the timing of the treatment, the learning or thestorage of the information about the young animal can be influenced bythe substance. After a fixed period (retention), the test is repeated(trial 2). A larger difference between the investigation times measuredin trials 1 and 2 means that the adult animal has remembered the younganimal better.

The compounds of the invention of the general formula (I) are suitablefor use as medicaments for humans and animals.

The present invention also includes pharmaceutical preparations which,besides inert, nontoxic, pharmaceutically suitable excipients andcarriers, contain one or more compounds of the general formula (I), orwhich consist of one or more compounds of the formula (I), and toprocesses for producing these preparations.

The compounds of the formula (I) are to be present in these preparationsin a concentration of from 0.1 to 99.5% by weight, preferably from 0.5to 95% by weight, of the complete mixture.

Besides the compounds of the formula (I), the pharmaceuticalpreparations may also contain other active pharmaceutical ingredients.

The abovementioned pharmaceutical preparations can be produced by knownmethods in a conventional way, for example using the excipient(s) orcarrier(s).

The novel active ingredients can be converted in a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese cases, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of the completemixture, i.e. in amounts which are sufficient to reach the stated doserange.

The formulations are produced for example by extending the activeingredients with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible for example when wateris used as diluent where appropriate to use organic solvents asauxiliary solvents.

Administration can take place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight or of themode of administration, of the individual behavior towards themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered, it may be advisable to divide theseinto a plurality of single doses over the day.

Abbreviations: DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide HOBt1-Hydroxy-1H-benzotriazole × H₂O NMR Nuclear magnetic resonancespectroscopy RT Room temperature TBTUO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate THFTetrahydrofuran

LC-MS Method: MS apparatus type: Micromass Platform LCZ Ionization: ESIpositive HPLC apparatus type: HP 1100 UV detector DAD: 208-400 nm Oventemp.: 40° C. Column: Symmetry C 18 50 mm × 2.1 mm; 3.5 μm Gradient:Time (min) A: % B: % Flow rate (ml/min) 0.00 10.0 90.0 0.50 4.00 90.010.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50A: Acetonitrile + 0.1% formic acidB: Water + 0.1% formic acidStarting Compounds:

EXAMPLE 1A 3-Quinuclidinecarbonyl chloride Hydrochloride

3-Quinuclidinecarboxylic acid hydrochloride was prepared as described byOrlek et al. J. Med. Chem. 1991, 34, 2726.

500 mg (2.61 mmol) of 3-quinuclidinecarboxylic acid are heated togetherwith 1.9 ml (26.09 mmol) of thionyl choride under reflux for 2 h. Thereaction mixture is freed of excess thionyl chloride under reducedpressure. 20 ml portions of toluene are added twice and evaporated todryness each time. The product obtained in this way is reactedimmediately without further purification.

EXAMPLE 2 7-Bromo-1-benzothiophen-2-amine

156 mg (0.61 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid aremixed with 156.8 mg (1.21 mmol) of N,N-diisopropylethylamine in 4.0 mlof DMF. At 0° C., 183.7 mg (0.67 mmol) of diphenyl phosphorazidate areadded. The reaction mixture is left to stand at 8° C. overnight and thenstirred into ice-water. It is neutralized with acetic acid, and theresulting precipitate is filtered off with suction and carefully driedat 40° C. The solid is then suspended in xylene and heated under refluxfor 1 h. The solvent is removed under reduced pressure, and the residueis put in water and heated for 3 h. The aqueous phase is extractedseveral times with ethyl acetate. The organic phase is dried over sodiumsulfate and then the solvent is removed under reduced pressure. 128 mgof the title compound are isolated in a purity which is suitable forfurther reactions. The amine is reacted further without furtherpurification.

LC-MS: R_(t) 5.25 min., MS (ESIpos): m/z=229 (M+H)⁺.

Exemplary Embodiments EXAMPLE 1 N-(2-Naphthyl)quinuclidine-3-carboxamideHydrochloride

740 mg (5.14 mmol) of 2-naphthylamine are added to a solution of 540 mg(2.57 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride andpyridine (620 mg, 4.8 mmol) in 3 ml of dimethylformamide at 0° C. Themixture is stirred at RT over night. It is worked up by concentratingand taken up in dichloromethane. The crude product is chromatographed onsilica gel (mobile phase: dichloromethane/methanol 10:1, 5:1). Theresulting product crystallizes from dichloromethane and is filtered offwith suction and dried.

Yield: 26% of theory of the hydrochloride

¹H-NMR (200,1 MHz, DMSO-d₆): δ=10.60 (br. s, 1H), 10.10 (br. s, 1H),8.35 (d, 1H), 7.95-7.75 (m, 3H), 7.65 (dd, 1H), 7.60-7.45 (m, 2H), 3.65(m, 1H), 3.45-,10 (m, 7H), 2.05-1.85 (m, 2H), 1.85-1.70 (m, 2H)

MS (ESIpos): m/z=281 (M+H)⁺ (free base)

LC-MS: R_(t)=2.65 min., MS (ESIpos): m/z=281 (M+H)⁺ (free base).

EXAMPLE 2 N-(6-Quinolinyl)quinuclidine-3-carboxamide Hydrochloride

172 mg (1.19 mmol) of 6-aminoquinoline are mixed with 461 mg (3.57 mmol)of N,N-diisopropylethylamine in 3 ml of DMF under argon at 0° C. 250 mg(2.57 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride aredissolved in a little dry DMF and added dropwise to the reaction mixtureat 0° C. It is then stirred at room temperature overnight. It is workedup by concentrating and taking up in dichloromethane. The crude productis chromatographed on silica gel 60 (mobile phase: dichloromethane/ethylacetate 10:1, then dichloromethane/methanol 10:1, 3:1). The productfractions are combined and finally purified by preparative HPLC (RP18column; mobile phase: acetonitrile/water, gradient 1:99→30:70).

Yield: 28 mg (7% of theory) of the hydrochloride

¹H-NMR (200,1 MHz, DMSO-d₆): δ=11.00 (br. s, 1H), 10.19 (br. s, 1H),9.06-9.04 (m, 1H), 8.88-8.85 (m, 1H), 8.70-8.68 (m, 1H), 8.27-8.23 (m,1H), 8.12-8.06 (m, 1H), 7.89-7.83 (m, 1H), 3.70-3.50 (m, 1H), 3.40-3.10(m, 7H), 2.00-1.80 (m, 2H), 1.80-1.65 (m, 2H)

MS (ESIpos): m/z=282 (M+H)⁺ (free base)

LC-MS: R_(t)=0.30 min., MS (ESIpos): m/z=282 (M+H)⁺ (free base).

EXAMPLE 3 N-(3a,7a-Dihydro-1H-indazol-6-yl)quinuclidine-3-carboxamidHydrochloride

In analogy to the method described in Example 2, 250 mg (2.57 mmol) of3-quinuclidinecarbonyl chloride, 461 mg (3.57 mmol) ofN,N-diisopropylethylamine, catalytic amounts of DMAP (approx. 1 mg) and158 mg (1.19 mmol) of 4-aminoindazole are reacted.

Yield: 55 mg (15% of theory) of the hydrochloride

¹H-NMR (200,1 MHz, DMSO-d₆): δ=10.55 (br. s, 1H), 10.05 (br. s, 1H),8.15 (s, 1H), 7.97 (d, 1H), 7.67 (d, 1H), 7.14 (dd, 1H), 3.70-3.60 (m,1H), 3.40-3.15 (m, 7H), 2.00-1.85 (m, 2H), 1.80-1.65 (m, 2H)

MS (ESIpos): m/z=271 (M+H)⁺ (free base).

EXAMPLE 4 N-(6-Quinoxalinyl)quinuclidine-3-carboxamide Hydrochloride

In analogy to the method described in Example 2, 250 mg (2.57 mmol) of3-quinuclidinecarbonyl chloride, 461 mg (3.57 mmol) ofN,N-diisopropylethylamine, catalytic amounts of DMAP (approx. 1 mg) and173 mg (1.19 mmol) of 6-quinoxalinylamine are reacted.

Yield: 58 mg (15% of theory) of the Hydrochloride

¹H-NMR (200,1 MHz, DMSO-d₆): δ=10.90 (s, 1H), 9.99 (br. s, 1H),8.90-8.88 (m, 2H), 8.84-8.83 (m, 2H), 8.10-7.94 (m, 2H), 3.60-3.50 (m,1H), 3.30-3.05 (m, 7H), 2.00-1.80 (m, 2H), 1.80-1.65 (m, 2H)

MS (ESIpos): m/z=283 (M+H)⁺ (free base).

1. Compounds of the general formula (I)

in which R¹ is a 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ringatoms, in which m and n are independently of one another 2 or 3, inwhich p is 1, 2 or 3, and where the bicycloalkyl radical is optionallysubstituted by (C₁-C₆)-alkyl, R² is 8- to 10-membered heteroaryl,naphthyl or azulenyl, where the rings are optionally substituted byradicals selected from the group of hydrogen, halogen, formyl,carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, and R³ is hydrogen or(C₁-C₆)-alkyl, and their salts, solvates and solvates of the salts. 2.Compounds as claimed in claim 1, where R¹ is1-azabicyclo[2.2.2]oct-3-yl, and R² and R³ have the meaning indicated inclaim
 1. 3. Compounds as claimed in claim 1 or 2, where R¹ is1-azabicyclo[2.2.2]oct-3-yl, R² is benzotriazolyl, benzothiophenyl,quinolinyl, benzopyrazinyl or naphthyl, where the rings are optionallysubstituted by 1 to 3 radicals selected from the group of hydrogen,halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, and R³ is hydrogen.
 4. A process forpreparing compounds of the general formula (1) as claimed in claim 1,characterized in that compounds of the general formula (II)R¹—CO—X  (II) in which R¹ has the abovementioned meaning, and X ishydroxyl or a suitable leaving group, are reacted with a compound of thegeneral formula (III)HNR¹R²  (III) in which R² and R³ have the abovementioned meaning, in aninert solvent, where appropriate in the presence of a condensing agentand where appropriate in the presence of a base.
 5. Compounds accordingto any one of claims 1 to 3 for the treatment and/or prophylaxis ofdiseases.
 6. Medicament comprising at least one compound according toany of claims 1 to 3 mixed with at least one pharmaceuticallyacceptable, essentially nontoxic carrier or excipient.
 7. Use ofcompounds according to any of claims 1 to 3 for producing a compositionfor improving perception, concentration, learning and/or memory.
 8. Useof compounds according to any of claims 1 to 3 for producing amedicament for the treatment and/or prophylaxis of impairments ofperception, concentration, learning and/or memory.
 9. Medicamentaccording to claim 6 for the treatment and/or prophylaxis of impairmentsof perception, concentration, learning and/or memory.